β-D-phenylthioxylosides, their method of preparation and their use as therapeutic agents

ABSTRACT

The present invention relates, by way of novel industrial products, to the β-D-phenylthioxyloside compounds of the formula ##STR1## in which: X represents a sulfur atom or an oxygen atom; 
     R 1 , R 2  and R 3 , which are identical or different, each represent a hydrogen atom, a nitro group, a cyano group, a group --CO--R (in which R represents a C 1  -C 4  alkyl group or a trifluoromethyl group), an amino group, an acetamido group (NHCOCH 3 ), a C 1  -C 4  alkoxy group, a trifluoromethyl group or a phenyl group substituted by one or more cyano, nitro or trifluoromethyl groups, it being possible for R 1  and R 2 , taken together, to form, with the phenyl group to which they are bonded, a β-naphthalenyl group which is unsubstituted or substituted by one or more cyano, nitro or trifluoromethyl groups; and 
     Y represents the hydrogen atom or an aliphatic acyl group. 
     These compounds are useful as therapeutic agents, especially as venous antithrombotics.

The present invention relates, by way of novel industrial products, tothe β-D-phenylthioxyloside compounds of formula I below. It furtherrelates to their method of preparation and their use in therapy asantithrombotics, especially venous antithrombotics.

European patent document B-0051023 has already disclosedbenzoylphenyloside and α-hydroxybenzylphenyloside derivatives as ulcerinhibitors, platelet aggregation inhibitors, antithrombotics andcerebral oxygenators.

Also, European patent document A-0133103 has disclosedbenzylphenylosides which are useful as hypocholesterolemics andhypolipidemics, some of these compounds, in particular the product ofExample 1, having antithrombotic effects as well.

It has now just been found that the β-D-phenylthioxyloside compoundsaccording to the invention, which are structurally different from theknown products of the prior art, are useful in the treatment andprevention of diseases associated with circulatory disorders, especiallyas venous antithrombotics.

The compounds according to the invention unexpectedly haveantithrombotic properties which are greatly superior to those of theknown products of the prior art; reference is made in this connection tothe results of the comparative experiments collated in Table I below.

The novel products according to the invention are selected from thegroup consisting of the β-D-phenylthioxylosides of the formula ##STR2##in which: X represents a sulfur atom or an oxygen atom;

R₁, R₂ and R₃, which are identical or different, each represent ahydrogen atom, a nitro group, a cyano group, a group --CO--R (in which Rrepresents a C₁ -C₄ alkyl group or a trifluoromethyl group), an aminogroup, an acetamido group (NHCOCH₃), a C₁ -C₄ alkoxy group, atrifluoromethyl group or a phenyl group substituted by one or morecyano, nitro or trifluoromethyl groups, it being possible for R₁ and R₂,taken together, to form, with the phenyl group to which they are bonded,a β-naphthalenyl group which is unsubstituted or substituted by one ormore cyano, nitro or trifluoromethyl groups; and

Y represents the hydrogen atom or an aliphatic acyl group.

The hydroxyl groups of the β-D-thioxylose residue are capable of beingacylated, especially acetylated. The present invention thereforeincludes the derivatives of formula I in which the hydroxyl groups ofthe β-D-thioxylose residue are acylated, especially acetylated.

Among the aliphatic acyl groups which are suitable according to theinvention, there may be mentioned those which contain a total of 2 to 5carbon atoms, the preferred aliphatic acyl group being CH₃ CO.

C₁ -C₄ alkyl group is understood here as meaning a linear or branchedhydrocarbon radical containing 1 to 4 carbon atoms, the preferred alkylgroup being the methyl group.

C₁ -C₄ alkoxy group is understood here as meaning an alkoxy group inwhich the linear or branched hydrocarbon radical contains 1 to 4 carbonatoms, the preferred alkoxy group being the methoxy group.

The preferred compounds according to the invention are the compounds offormula I in which:

X represents a sulfur atom or an oxygen atom;

R₁ represents the hydrogen atom;

at least one of the radicals R₂ and R₃ represents a cyano group or R₂represents the hydrogen atom and R₃ represents a 4-acetyl group, a4-acetamido group or a 2-nitro group; and

Y represents the hydrogen atom or a C₂ -C₅ aliphatic acyl group.

The compounds of formula I and the corresponding acylated compounds canbe prepared by means of a glycosylation reaction which comprises:

(i) reacting a compound of the formula ##STR3## in which X, R₁, R₂ andR₃ are as defined above, with a thioxylose derivative selected from thegroup consisting of:

(i) the acylthioxylosyl halides of the formula ##STR4## (ii) theperacylated thioxyloses of the formula ##STR5## and (iii) theacylthioxylosyl trichloroacetimidates of the formula ##STR6## in whichHal represents a halogen atom such as Cl or Br (the bromine atom beingthe preferred halogen atom here) and Y represents an acyl group,especially an aliphatic acyl group containing a total of 2 to 5 carbonatoms and preferably the acetyl group,

in an inert solvent, at a rate of 1 mol of II to about 0.6 to 1.2 mol ofcompound III, IV or V, in the presence of an acid acceptor and/or aLewis acid; and

(ii) if necessary, carrying out a deacylation reaction at a temperaturein the range from 0° C. to the reflux temperature in the range from 0°C. to the reflux temperature of the reaction medium, in a C₁ -C₄ loweralcohol (preferably methanol), in the presence of a metal alcoholate(preferably magnesium methylate or sodium methylate), to give a compoundof formula I in which Y is H.

Compounds III, IV and V can be in the α or β configuration or in theform of an anomeric mixture of both configurations.

The glycosylation reactions of phenols and thiophenols II were carriedout either starting from compound III in the presence of a catalyst suchas salts or oxides of silver, mercury or zinc, or starting from compoundV in the presence of a Lewis acid, especially boron trifluoride etherateor zinc chloride, or starting from compound IV in the presence of aLewis acid.

According to one preferred way of carrying out the invention, it isrecommended to condense 1 mol of phenol or thiophenol II with about 1.1to 1.2 mol of acylthioxylosyl halide III in an inert solvent selectedfrom polar or apolar solvents (for example dimethylformamide,tetrahydrofuran, dioxane, acetonitrile, nitromethane, benzene, toluene,xylenes and mixtures thereof), in the presence of mercuric cyanide.

It will be advantageous to use2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide in abenzene/nitromethane mixture (1/1 v/v), in the presence of 1.1 to 1.3mol of mercuric cyanide, at a temperature in the range from 0° C. to thereflux temperature of the reaction medium, preferably at about 40°-50°C., for 1 to 4 hours, preferably for about 2 hours.

According to a second preferred way of carrying out the invention, it isrecommended to condense 1 mol of phenol or thiophenol II with about 1.1to 1.2 mol of acylthioxylosyl halide III in an inert solvent (forexample methylene chloride or acetonitrile), in the presence of silverimidazolate and zinc chloride.

It will be advantageous to use 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosylbromide in methylene chloride or a methylene chloride/acetonitrilemixture, in the presence of 1.5 to 1.7 mol of silver imidazolate and 2to 2.2 mol of zinc chloride, at a temperature in the range from 0° C. tothe reflux temperature of the reaction medium, preferably at about40°-60° C., for 24 to 48 hours.

According to a third preferred way of carrying out the invention, it isrecommended to condense 1 mol of phenol or thiophenol II with about 0.6to 1 mol of acylthioxylosyl halide III in an inert solvent (for exampletoluene and/or acetonitrile), in the presence of zinc oxide.

It will be advantageous to use 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosylbromide in a toluene/acetonitrile mixture, in the presence of 0.5 to 1.2mol of zinc oxide, at a temperature in the range from room temperatureto the reflux temperature of the reaction medium, preferably at about40°-60° C., for 18 to 48 hours.

According to a fourth preferred way of carrying out the invention, it isrecommended to condense 1 mol of phenol or thiophenol II with about 1.1to 1.3 mol of acylthioxylosyl trichloroacetimidate in an inert solvent(for example methylene chloride), in the presence of boron trifluorideetherate.

It will be advantageous to use2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl trichloroacetimidate inmethylene chloride, in the presence of 0.1 to 0.4 mol of borontrifluoride etherate dissolved in methylene chloride, or zinc chloride,at a temperature in the range from -40° C. to room temperature (15°-25°C.), preferably at about -20° C. to 0° C., for 1 to 5 hours.

In all cases the glycosylation reaction yields a mixture of the isomersof α and β configuration in variable proportions.

The isomer of β configuration is isolated by the methods known to thoseskilled in the art, for example fractional crystallization orchromatography, especially flash chromatography (i.e. chromatography ona silica column, under pressure, according to the technique described byW. C. STILL et al. in J. Org. Chem. (1978), 42 (no. 14) 2923).

If appropriate, the derivatives obtained are subjected to deacylation,more particularly to deacetylation, which is carried out at atemperature in the range from 0° C. to the reflux temperature of thereaction medium, in a C₁ -C₄ lower alcohol, in the presence of thecorresponding metal alcoholate. Preferably, methanol will be chosen asthe lower alcohol and sodium or magnesium methanolate as the metalalcoholate.

If desired, the deacylation reaction can be carried out afterglycosylation without isolation of the intermediate acylated compoundformed.

It is also possible to carry out the deacylation reaction enzymatically,for example using pork liver esterase.

The acylthioxylosyl halides of formula III of β configuration in which Yrepresents an aliphatic acyl group containing 2 to 5 carbon atoms arenovel compounds.

The acylthioxylosyl trichloroacetimidates of formula V in which Yrepresents an aliphatic acyl group containing 2 to 5 carbon atoms arenovel compounds.

To obtain the intermediate thiophenols of formula II in which X=S, it isrecommended to:

(i) condense dimethylaminothiocarbamoyl chloride of the formula ##STR7##in a strong basic medium, with a phenol of the formula ##STR8## in whichR₁, R₂ and R₃ are as defined above, to give a compound of the formula##STR9## in which R₁, R₂ and R₃ are as defined above;

(ii) subject the resulting compound of formula VII to a Newmannrearrangement (J. Org. Chem. (1966) 31, p. 3980), by heating, to give acompound of the formula ##STR10## in which R₁, R₂ and R₃ are as definedabove; and

(iii) treat the resulting compound of formula VIII with a metalalcoholate, preferably sodium or magnesium methanolate, in a C₁ -C₄lower alcohol, preferably methanol, dimethylformamide or dioxane, togive a thiophenol of formula II in which X=S.

The intermediate thiophenols can also be obtained by the nucleophilicsubstitution of an appropriate halogenobenzene according to the methoddescribed by L. TESTAFERRI in Tetrahedron Letters, vol. 21, p. 3099-3100(1980) or according to the method described by Paolo BATTISTONI inGazzetta Chimica Italiana, 110, p. 301 (1980).

The following thiophenols are novel compounds:3,5-bis(trifluoromethyl)benzenethiol, 3-cyano-4-mercaptobenzonitrile,6-mercaptonaphthalene-2-carbonitrile and3,5-dicyano-2-mercaptobenzonitrile.

The following dimethylthiocarbamates are novel compounds:O-4-trifluoromethylphenyl dimethylthiocarbamate, O-3-cyanophenyldimethylthiocarbamate, O-2-cyanophenyl dimethylthiocarbamate,O-2-(6-cyanonaphthalenyl)dimethylthiocarbamate, O-3,4,5-trimethoxyphenyldimethylthiocarbamate, O-2-trifluoromethylphenyl dimethylthiocarbamate,O-3,5-bis(trifluoromethyl)phenyl dimethylthiocarbamate,O-2,4-dicyanophenyl dimethylthiocarbamate, O-4-(4-cyanophenyl)phenyldimethylthiocarbamate, O-2,4,6-tricyanophenyl dimethylthiocarbamate,S-4-trifluoromethylphenyl dimethylthiocarbamate, S-3-cyanophenyldimethylthiocarbamate, S-2-cyanophenyl dimethylthiocarbamate,S-2-(6-cyanonaphthalenyl)dimethylthiocarbamate, S-3,4,5-trimethoxyphenyldimethylthiocarbamate, S-2-trifluoromethylphenyl dimethylthiocarbamate,S-3,5-bis(trifluoromethyl)phenyl dimethylthiocarbamate,S-2,4-dicyanophenyl dimethylthiocarbamate, S-4-(4-cyanophenyl)phenyldimethylthiocarbamate and S-2,4,6-tricyanophenyl dimethylthiocarbamate.

According to the invention, a therapeutic composition is proposed whichcontains, in association with a physiologically acceptable excipient, atleast one compound selected from the group consisting of the products offormula I. Of course, in such a composition, the active ingredient ispresent in a therapeutically effective amount.

The compounds of formula I are useful in therapy as antithrombotics.They are particularly useful in the prevention and treatment ofdisorders of the venous circulation.

According to the invention, it is recommended to use a substancebelonging to the group consisting of the compounds of formula I in orderto obtain an antithrombotic drug for use in therapy to combat disordersof the venous circulation.

Further characteristics and advantages of the invention will beunderstood more clearly from the following description of PreparatoryExamples, which in no way imply a limitation and are given by way ofillustration, and results of pharmacological experiments.

In the following Preparatory Examples, the α or β configuration has beenspecified in the compound names in cases where said configuration wasdetermined. Where the configuration is not indicated, this means thatthe corresponding product is an anomeric mixture of the α and βconfigurations in proportions which were not determined.

PREPARATION I Preparation of 4-cyanophenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 1a)

Under an inert atmosphere, a mixture of 70 ml of anhydrous benzene, 70ml of nitromethane and 15 g of a 0.4 nm molecular sieve (marketed by E.MERCK) is stirred at room temperature (15°-25° C.) for 0.25 h and 12 g(47.10⁻³ mol) of Hg(CN)₂ are then added. After the resulting mixture hasbeen stirred for 10 minutes at room temperature, 16.9 g (47.10⁻³ mol) of2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and then 6 g(43.10⁻³ mol) of 4-mercaptobenzonitrile are added in small portions.When the addition is complete, the reaction mixture is heated at 40°-50°C. for 8 hours and then filtered on Celite® (i.e. diatomaceous silicafor filtration). The residue is washed several times with ethyl acetate.The organic phase is collected and washed successively with a 1N aqueoussolution of hydrochloric acid, a 1N aqueous solution of sodium hydroxideand a saturated solution of sodium chloride and then with water untilthe pH of the washings is neutral; it is dried over magnesium sulfateand filtered and the solvent is evaporated off. The crude productobtained is recrystallized from an ethyl acetate/petroleum ether mixtureto give 8.65 g (yield: 49%) of the product of β configuration.

M.p.=155° C.

[α]_(D) ²⁰ C. =+37° (c=0.5; CHCl₃)

PREPARATION II Preparation of 4-cyanophenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 1a)

A suspension of 625 mg (1.76.10⁻³ mol) of2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide, 200 mg (1.48.10⁻³mol) of 4-mercaptobenzonitrile and a 400 pm molecular sieve in 10 ml ofacetonitrile is stirred in the presence of 605 mg (4.4.10⁻³ mol) of zincchloride and 310 mg (1.8.10⁻³ mol) of silver imidazolate, in the absenceof light, under an inert atmosphere. After heating at 50° C. for 3 h,the reaction mixture is filtered on Celite® in ethyl acetate. Thefiltrate is washed with a 1N solution of hydrochloric acid, water, a 1Nsolution of sodium hydroxide, water and finally a saturated solution ofsodium chloride, dried over magnesium sulfate and evaporated underreduced pressure. After purification by chromatography on silica gelusing a hexane/ethyl acetate mixture (3/1 v/v) as the eluent, andprecipitation in ether, 100 mg (yield: 17%) of the expected product areobtained.

M.p.=155° C.

PREPARATION III Preparation of 4-cyanophenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 1a)

A suspension of 192 mg (0.44.10⁻³ mol) of2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl trichloroacetimidate, 71 mg(0.52.10⁻³ mol) of 4-mercaptobenzonitrile, 20 mg (0.15.10⁻³ mol) of zincchloride and a 400 pm sieve in 2 ml of acetonitrile is stirred for 4 hunder an inert atmosphere. The reaction mixture is then filtered onCelite® in ethyl acetate and subsequently washed with a 1N solution ofsodium hydroxide, water and finally a saturated solution of sodiumchloride, dried over magnesium sulfate and evaporated under reducedpressure. After precipitation in ether, 42 mg (yield: 23%) of theexpected product are obtained.

M.p.=155° C.

PREPARATION IV Preparation of 4-cyanophenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 1a)

A suspension of 16.9 g (47.10⁻³ mol) of2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 6 g (43.10⁻³ mol)of 4-mercaptobenzonitrile and 3.5 g (43.10⁻³ mol) of zinc oxide (ZnO) in120 ml of anhydrous toluene and 120 ml of acetonitrile is stirred underan inert atmosphere, in the presence of a molecular sieve (1 mm), for 18hours, at 50° C. After the reaction medium has been filtered on Celite®in ethyl acetate, the organic phase obtained is washed with a 1Nsolution of HCl twice, a 1N solution of sodium hydroxide and finallywater, dried over magnesium sulfate and evaporated under reducedpressure. After precipitation in ether, 11.30 g (yield: 64%) of theexpected product are obtained.

M.p.=155° C.

PREPARATION V Preparation of 4-cyanophenyl 1,5-dithio-β-D-xylopyranoside(Example 1)

Under a nitrogen atmosphere, 8.5 g (21.10⁻³ mol) of 4-cyanophenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 1a) aresuspended in 100 ml of methanol, and 2 ml of sodium methylate (8% w/v ofNa in methanol) are then added. The reaction medium is stirred at roomtemperature until the starting material has completely dissolved (2hours) and is then neutralized by the addition of Amberlite® IR 120 H⁺resin. The methanol is evaporated off under reduced pressure; the crudeproduct obtained is recrystallized from an ethanol/water mixture (65/25v/v) to give 5.3 g (yield: 89.7%) of the expected product.

M.p.=175° C.

[α]_(D) ²⁰° C. =+35.8° (c=0.5; CH₃ OH)

PREPARATION VI Preparation of 4-nitrophenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 2a)

If the procedure described in Preparation I is followed starting from 6g (38.10⁻³ mol) of 4-nitrobenzenethiol, 10.7 g (42.10⁻³ mol) of mercuriccyanide, Hg(CN)₂, and 15.1 g (42.10⁻³ mol) of2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 10.8 g (yield: 66%)of the expected product are obtained.

M.p.=182° C.

[α]_(D) ²⁰° C. =+50.8° (c=0.64; CHCl₃)

PREPARATION VII Preparation of 4-nitrophenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 2a)

If the procedure described in Preparation IV is followed starting from 6g (38.10⁻³ mol) of 4-nitrobenzenethiol, 15.1 g (42.10⁻³ mol) of2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 3.2 g (39.10⁻³mol) of zinc oxide (ZnO), 13 g (yield: 79%) of the expected product areobtained after precipitation in ether.

M.p.=182° C.

PREPARATION VIII Preparation of 4-nitrophenyl1,5-dithio-β-D-xylopyranoside (Example 2)

If the procedure described in Preparation V is followed starting from10.3 g (24.10⁻³ mol) of 4-nitrophenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 2a), 5.4 g(yield: 74%) of the expected product are obtained afterrecrystallization from an ethanol/water mixture (1/1 v/v).

M.p.=168° C.

[α]_(D) ²⁰° C. =+54° (c=0.64; CH₃ OH)

PREPARATION IX Preparation of 2-naphthalenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 3a)

If the procedure described in Preparation I is followed starting from6.8 g (42.4.10⁻³ mol) of naphthalene-2-thiol, 10.8 g (42.4.10⁻³ mol) ofmercuric cyanide, Hg(CN)₂, and 12 g (33.2.10⁻³ mol) of2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 5.84 g (yield: 40%)of the expected product are obtained.

M.p.=151° C.

[α]_(D) ²⁰° C. =-41.5° (c=1.6; CHCl₃)

PREPARATION X Preparation of 2-naphthalenyl1,5-dithio-β-D-xylopyranoside (Example 3)

If the procedure described in Preparation V is followed starting from5.8 g (13.10⁻³ mol) of 2-naphthalenyl2,3,4-tri-O-acetyl-1,5-dithio-α-D-xylopyranoside (Example 3a), 3.45 g(yield: 86%) of the expected product are obtained afterrecrystallization from an ethanol/water mixture (4/1 v/v).

M.p.=163°-164° C.

[α]_(D) ²⁰° C. =+31.1° (c=0.9; CH₃ OH)

PREPARATION XI Preparation of O-4-trifluoromethylphenyldimethylthiocarbamate

10 g (62.10⁻³ mol) of 4-trifluoromethylphenol are added to a solution of3.63 g (65.10⁻³ mol) of potassium hydroxide in 100 ml of water and 100ml of acetone. The mixture obtained is stirred for 45 minutes at roomtemperature and then cooled to 0° C. before the addition of 8.77 g(71.10⁻³ mol) of dimethylthiocarbamoyl chloride. The resulting reactionmedium is subsequently stirred for 4 hours at room temperature and thenhydrolyzed. The expected product is extracted with ethyl acetate. Theresulting organic phase is washed with a 1N aqueous solution of sodiumhydroxide, then a 1N aqueous solution of hydrochloric acid and finallywater, after which it is dried and evaporated under reduced pressure togive 17 g (quantitative yield) of the expected product.

PREPARATION XII Preparation of S-4-trifluoromethylphenyldimethylthiocarbamate

Under a nitrogen atmosphere, 17 g (68.10⁻³ mol) ofO-4-trifluoromethylphenyl dimethylthiocarbamate are heated at 220° C.for 5 hours. After purification by flash chromatography using atoluene/ethyl acetate mixture (8/1 v/v) as the eluent, 13 g (yield: 80%)of the expected product are obtained.

PREPARATION XIII Preparation of 4-trifluoromethylbenzenethiol

Under a nitrogen atmosphere, 12 g (48.10⁻³ mol) ofS-4-trifluoromethylphenyl dimethylthiocarbamate are dissolved in 125 mlof dimethylformamide. The solution obtained is cooled to 0° C. and 25 mlof an 18% solution of sodium methylate in methanol are then added. Afterstirring for 1.5 hours, the reaction medium is hydrolyzed in a 1Nhydrochloric acid/ice mixture and then extracted with ethyl acetate. Theorganic phase obtained is washed with water, dried over magnesiumsulfate and then evaporated under reduced pressure. 6.2 g (yield: 67%)of the expected product are obtained after purification by flashchromatography using a hexane/ethyl acetate mixture (8/1 v/v) as theeluent.

PREPARATION XIV Preparation of 4-trifluoromethylphenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 4a)

If the procedure described in Preparation I is followed starting from5.58 g (32.10⁻³ mol) of 4-trifluoromethylbenzenethiol, 8.87 g (35.10⁻³mol) of mercuric cyanide, Hg(CN)₂, and 12.3 g (35.10⁻³ mol) of2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 6.2 g (yield: 40%)of the expected product are obtained.

M.p.=160° C.

[α]_(D) ²⁰° C. =+16° (c=0.5; CHCl₃)

PREPARATION XV Preparation of 4-trifluoromethylphenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 4a)

If the procedure described in Preparation IV is followed starting from5.6 g (32.10⁻³ mol) of 4-trifluoromethylbenzenethiol, 12.3 g (35.10⁻³mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 2.55 g(32.10⁻³ mol) of zinc oxide (ZnO), 7.4 g (yield: 48%) of the expectedproduct are obtained after precipitation in ether.

M.p.=160° C.

PREPARATION XVI Preparation of 4-trifluoromethylphenyl1,5-dithio-β-D-xylopyranoside (Example 4)

If the procedure described in Preparation V is followed starting from6.2 g (14.10⁻³ mol) of 4-trifluoromethylphenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 4a), 2.05 g(yield: 45%) of the expected product are obtained after purification byflash chromatography using a CHCl₃ /CH₃ OH mixture (4/1 v/v) as theeluent.

M.p.=128°-130° C.

[α]_(D) ²³° C. =+10° (c=0.5; CH₃ OH)

PREPARATION XVII Preparation of O-3-cyanophenyl dimethylthiocarbamate

If the procedure described in Preparation XI is followed starting from15 g (126.10⁻³ mol) of 3-hydroxybenzonitrile, 17.9 g (145.10⁻³ mol) ofdimethylthiocarbamoyl chloride and 7.4 g (132.10⁻³ mol) of potassiumhydroxide, 29 g (quantitative yield) of the expected product areobtained.

M.p.=108° C.

PREPARATION XVIII Preparation of S-3-cyanophenyl dimethylthiocarbamate

If the procedure described in Preparation XII is followed starting from29 g (141.10⁻³ mol) of O-3-cyanophenyl dimethylthiocarbamate, 19 g(yield: 65.5%) of the expected product are obtained.

M.p.=104° C.

PREPARATION XIX Preparation of 3-mercaptobenzonitrile

If the procedure described in Preparation XIII is followed starting from19 g (92.10⁻³ mol) of O-3-cyanophenyl dimethylthiocarbamate, 10.3 g(yield: 83.1%) of the expected product, melting at 91°-95° C., areobtained.

PREPARATION XX Preparation of 3-cyanophenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 5a)

If the procedure described in Preparation I is followed starting from9.3 g (67.10⁻³ mol) of 3-mercaptobenzonitrile, 18 g (73.10⁻³ mol) ofmercuric cyanide, Hg(CN)₂, and 26.14 g (73.10⁻³ mol) of2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 8.55 g of theexpected product are obtained.

M.p.=133° C.

[α]_(D) ²⁰° C. =+0.9° (c=0.44; CHCl₃)

PREPARATION XXI Preparation of 3-cyanophenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 5a)

If the procedure described in Preparation IV is followed starting from10.3 g (74.1.10⁻³ mol) of 3-mercaptobenzonitrile, 28.94 g (81.5.10⁻³mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 6.05 g(74.3.10⁻³ mol) of zinc oxide (ZnO), 9.6 g (yield: 31%) of the expectedproduct are obtained.

M.p.=133° C.

PREPARATION XXII Preparation of 3-cyanophenyl1,5-dithio-β-D-xylopyranoside (Example 5)

If the procedure described in Preparation V is followed starting from8.50 g (20.10⁻³ mol) of 3-cyanophenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside, 3.10 g (yield: 54.3%)of the expected product are obtained after recrystallization frommethanol.

M.p.=194°-195° C.

[α]_(D) ²⁰° C. =-5.4° (c=0.48; CH₃ OH)

PREPARATION XXIII Preparation of O-2-cyanophenyl dimethylthiocarbamate

If the procedure described in Preparation XVI is followed starting from15 g (126.10⁻³ mol) of 2-hydroxybenzonitrile, 17.9 g (145.10⁻³ mol) ofdimethylthiocarbamoyl chloride and 7.4 g (126.10⁻³ mol) of potassiumhydroxide, 24.1 g (yield: 94%) of the expected product are obtained.

M.p.=112° C.

PREPARATION XXIV Preparation of S-2-cyanophenyl dimethylthiocarbamate

If the procedure described in Preparation XII is followed starting from28 g (136.10⁻³ mol) of O-2-cyanophenyl dimethylthiocarbamate, 20 g(yield: 71.4%) of the expected product are obtained.

M.p.=70° C.

PREPARATION XXV Preparation of 2-mercaptobenzonitrile

If the procedure described in Preparation XIII is followed starting from20 g (97.10⁻³ mol) of S-2-cyanophenyl dimethylthiocarbamate, 10.9 g(yield: 83.2%) of the expected product are obtained in the form of anoil.

n_(D) =1.496

PREPARATION XXVI Preparation of 2-cyanophenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 6a)

If the procedure described in Preparation I is followed starting from9.70 g (72.10⁻³ mol) of 2-mercaptobenzonitrile, 19.45 g (77.10⁻³ mol) ofmercuric cyanide, Hg(CN)₂, and 27.4 g (77.10⁻³ mol) of2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 14.7 g (yield: 50%)of the expected product are obtained.

M.p.=160° C.

[α]_(D) ²⁰° C. =-45.5° (c=0.4; CHCl₃)

PREPARATION XXVII Preparation of 2-cyanophenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 6a)

If the procedure described in Preparation IV is followed starting from10.7 g (79.2.10⁻³ mol) of 2-mercaptobenzonitrile, 30.2 g (85.10⁻³ mol)of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 6.3 g(77.4.10⁻³ mol) of zinc oxide (ZnO), 19.3 g (yield: 60%) of the expectedproduct are obtained after crystallization from ether.

M.p.=160° C.

PREPARATION XXVIII Preparation of 2-cyanophenyl1,5-dithio-β-D-xylopyranoside (Example 6)

If the procedure described in Preparation V is followed starting from14.5 g (35.10⁻³ mol) of 2-cyanophenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 6a), 8.39 g(yield: 84.6%) of the expected product are obtained afterrecrystallization from methanol.

M.p.=118°-119° C.

[α]_(D) ²⁰° C. =+12.5° (c=0.52; CH₃ OH)

PREPARATION XXIX

Preparation of 2-nitrobenzenethiol

15.24 g (63.4.10⁻³ mol) of sodium sulfide (Na₂ S.9H₂ O) are added to asolution of 10 g (63.4.10⁻³ mol) of 2-chloronitrobenzene. The solutionobtained is stirred at room temperature for 12 hours. The reactionmedium is hydrolyzed in an ice/1N hydrochloric acid mixture. The yellowprecipitate formed is filtered off and the mother liquors are extractedwith ethyl acetate. The resulting organic phase is washed with wateruntil the pH of the washings is neutral, dried over magnesium sulfateand evaporated under reduced pressure to give 5.2 g of an oil, which areadded to the 3.8 g of precipitate. These 9 g of resulting product arepurified by chromatography on silica using a hexane/acetone mixture(95/5 v/v) as the eluent to give 6.02 g (yield: 61%) of the expectedproduct.

PREPARATION XXX Preparation of 2-nitrophenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 7a)

If the procedure described in Preparation I is followed starting from 6g (38.7.10⁻³ mol) of 2-nitrobenzenethiol, 10.75 g (42.5.10⁻³ mol) ofmercuric cyanide, Hg(CN)₂, and 15.12 g (42.10⁻³ mol) of2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 8 g (yield: 48%) ofthe expected product are obtained.

M.p.=176° C.

[α]_(D) ²⁰° C. =+15° (c=0.5; CH₂ Cl₂ /CH₃ OH (1/1 v/v))

PREPARATION XXXI Preparation of 2-nitrophenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 7a)

If the procedure described in Preparation IV is followed starting from6.1 g (39.3.10⁻³ mol) of 2-nitrobenzenethiol, 15.40 g (43.3.10⁻³ mol) of2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 3.68 g(45.2.10⁻³ mol) of zinc oxide (ZnO), 9.87 g (yield: 58%) of the expectedproduct are obtained.

PREPARATION XXXII Preparation of 2-nitrophenyl1,5-dithio-β-D-xylopyranoside (Example 7)

If the procedure described in Preparation V is followed starting from 8g (18.6.10⁻³ mol) of 2-nitrophenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 7a), 4.68 g(yield: 83.2%) of the expected product are obtained afterrecrystallization from methanol.

M.p.=185° C.

[α]_(D) ²⁰° C. =+12.4° (c=0.5; CH₂ Cl₂ /CH₃ OH (1/1 v/v))

PREPARATION XXXIII Preparation ofO-2-(6-cyanonaphthalenyl)dimethylthiocarbamate

2.85 g (51.10⁻³ mol) of potassium hydroxide pellets are added to asuspension of 8.05 g (47.10⁻³ mol) of2-hydroxynaphthalene-6-carbonitrile in 50 ml of acetone and 90 ml ofwater. The reaction mixture is heated at 50° C. for thirty minutes, withvigorous stirring. The mixture is then cooled to 0° C. and 6.46 g(52.10⁻³ mol) of dimethylthiocarbamoyl chloride in 80 ml of acetone areadded dropwise. When the addition is complete, the reaction medium isstirred for three hours at room temperature. It is concentrated byevaporation under reduced pressure and then hydrolyzed. 11.3 g (yield:94%) of the expected product are obtained after filtration of theprecipitate.

M.p.=153°-154° C.

PREPARATION XXXIV Preparation ofS-2-(6-cyanonaphthalenyl)dimethylthiocarbamate

Under a nitrogen atmosphere, 10 g (39.10⁻³ mol) ofO-2-(6-cyanonaphthalenyl)dimethylthiocarbamate are heated at 250° C. forsix hours, with stirring. The disappearance of the starting material ismonitored by thin layer chromatography using an ethyl acetate/toluenemixture (1/4 v/v) as the eluent. 7.6 g (yield: 76%) of the expectedproduct are obtained.

M.p.=166°-168° C.

PREPARATION XXXV Preparation of 6-mercaptonaphthalene-2-carbonitrile

Under a nitrogen atmosphere, 7.15 g (27.9.10⁻³ mol) ofO-2-(6-cyanonaphthalenyl)dimethylthiocarbamate are suspended in 50 ml ofdioxane, with stirring, and 16 ml (55.8.10⁻³ mol) of sodium methylate(8% w/v solution of Na in methanol) are then added to the mixture. Thereaction medium is stirred at 21° C. for two hours and monitored by thinlayer chromatography using an ethyl acetate/toluene mixture (1/3 v/v) asthe eluent. The reaction medium is hydrolyzed in an ice/concentrated HClmixture and the precipitate formed is filtered off to give 5.4 g (yield:100%) of the expected product.

M.p.=113°-115° C.

PREPARATION XXXVI Preparation of 2-(6-cyanonaphthalenyl)2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 8a)

If the procedure described in Preparation I is followed starting from 5g (27.10⁻³ mol) of 6-mercaptonaphthalene-2-carbonitrile, 7.5 g (29.10⁻³mol) of mercuric cyanide, Hg(CN)₂, and 12 g (32.10⁻³ mol) of2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 1.6 g (yield:12.9%) of the expected product are obtained.

M.p.=228°-230° C.

[α]_(D) ²³° C. =+73.4° (c=0.5; CHCl₃)

PREPARATION XXXVII Preparation of 2-(6-cyanonaphthalenyl)2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 8a)

If the procedure described in Preparation IV is followed starting from 5g (27.10⁻³ mol) of 6-mercaptonaphthalene-2-carbonitrile, 12 g (32.4.10⁻³mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 2.2 g(27.10⁻³ mol) of zinc oxide (ZnO), 1.5 g of the expected product areobtained after precipitation in ether.

M.p.=228°-230° C.

PREPARATION XXXVIII Preparation of 2-(6-cyanonaphthalenyl)1,5-dithio-β-D-xylopyranoside (Example 8)

If the procedure described in Preparation V is followed starting from1.27 g (2.76.10⁻³ mol) of 2-(6-cyanonaphthalenyl)2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 8a), 0.340 g(yield: 37%) of the expected product is obtained after recrystallizationfrom a methanol/chloroform mixture (1/1 v/v).

M.p.=226°-228° C.

[α]_(D) ²⁴° C. =+45.9° (c=0.3; DMSO)

PREPARATION XXXIX Preparation of phenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 9a)

If the procedure described in Preparation I is followed starting from 4g (36.3.10⁻³ mol) of benzenethiol, 14 g (39.4.10⁻³ mol) of2,3,4-tri-O-acetyl-5-thio-α-xylopyranosyl bromide and 10 g (39.10⁻³ mol)of mercuric cyanide (Hg(CN)₂), 7.3 g of the expected product areobtained after crystallization from ether.

M.p.=130° C.

[α]_(D) ²⁰° C. =+14.6° (c=0.5; CHCl₃)

PREPARATION XL Preparation of phenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 9a)

If the procedure described in Preparation IV is followed starting from 4g (36.3.10⁻³ mol) of benzenethiol, 15 g (42.3.10⁻³ mol) of2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 3 g (36.8.10⁻³mol) of zinc oxide (ZnO), 4.5 g (yield: 32.29%) of the expected productare obtained after crystallization from ether.

M.p.=130° C.

PREPARATION XLI Preparation of phenyl 1,5-dithio-β-D-xylopyranoside(Example 9)

If the procedure described in Preparation V is followed starting from6.9 g (18.10⁻³ mol) of phenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 9a), 3.7 g(yield: 80%) of the expected product are obtained afterrecrystallization from an ethanol/water mixture (50/10 v/v).

M.p.=150°-151° C.

[α]_(D) ²⁰° C. =-6° (c=0.5; CH₃ OH)

PREPARATION XLII Preparation of 3,4,5-trimethoxyphenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 10a)

If the procedure described in Preparation I is followed starting from11.35 g (57.10⁻³ mol) of 3,4,5-trimethoxybenzenethiol, 14.32 g (57.10⁻³mol) of mercuric cyanide, Hg(CN)₂, and 22.15 g (62.10⁻³ mol) of2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 7.52 g (yield: 28%)of the expected product are obtained.

M.p.=101° C.

[α]_(D) ²⁵° C. =-43° (c=0.2; CH₃ OH)

PREPARATION XLIII Preparation of 3,4,5-trimethoxyphenyl1,5-dithio-β-D-xylopyranoside (Example 10)

If the procedure described in Preparation V is followed starting from4.65 g (9.8.10⁻³ mol) of 3,4,5-trimethoxyphenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 10a), 2.4 g(yield: 70%) of the expected product are obtained afterrecrystallization from a methanol/water mixture (1/1 v/v).

M.p.=166° C.

[α]_(D) ²⁰° C. =-12° (c=0.2; CH₃ OH)

PREPARATION XLIV Preparation of 4-acetylphenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 11a)

If the procedure described in Preparation I is followed starting from1.03 g (6.7.10⁻³ mol) of 4-mercaptoacetophenone, 1.72 g (6.8.10⁻³ mol)of mercuric cyanide, Hg(CN)₂, and 2.65 g (7.5.10⁻³ mol) of2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 0.36 g (yield:12.5%) of the expected product is obtained.

M.p.=122° C.

[α]_(D) ²²° C. =+46.5° (c=0.29; CHCl₃)

PREPARATION XLV Preparation of 4-acetylphenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 11a)

If the procedure described in Preparation IV is followed starting from1.27 g (8.43.10⁻³ mol) of 4-mercaptoacetophenone, 3.27 g (9.2.10⁻³ mol)of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 0.68 g(8.35.10⁻³ mol) of zinc oxide (ZnO), 0.42 g (yield: 11%) of the expectedproduct is obtained.

M.p.=122° C.

PREPARATION XLVI Preparation of 4-acetylphenyl1,5-dithio-β-D-xylopyranoside (Example 11)

If the procedure described in Preparation V is followed starting from0.34 g (0.8.10⁻³ mol) of 4-acetylphenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 11a), 0.12 g(yield: 50%) of the expected product is obtained after recrystallizationfrom a methanol/water mixture (1/1 v/v).

M.p.=175° C.

[α]_(D) ²⁵° C. =+34° (c=0.2; CH₃ OH)

PREPARATION XLVII Preparation of 3-nitrophenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 12a)

If the procedure described in Preparation I is followed starting from 10g (64.5.10⁻³ mol) of 3-nitrobenzenethiol, 16.29 g (64.5.10⁻³ mol) ofmercuric cyanide (Hg(CN)₂) and 25.2 g (70.9.10⁻³ mol) of2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 7.44 g (yield: 27%)of the expected product are obtained after purification by flashchromatography using a toluene/ethyl acetate mixture (9/1 v/v) as theeluent, followed by crystallization from ether.

M.p.=121° C.

[α]_(D) ²⁰° C. =+1.8° (c=0.5; CH₃ OH)

PREPARATION XLVIII Preparation of 3-nitrophenyl1,5-dithio-β-D-xylopyranoside (Example 12)

If the procedure described in Preparation V is followed starting from7.18 g (16.7.10⁻³ mol) of 3-nitrophenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 12a), 3.9 g(yield: 77%) of the expected product are obtained.

M.p.=152°-154° C.

[α]_(D) ²⁰° C. =-3.6° (c=0.5; CH₃ OH)

PREPARATION IL Preparation of O-2-trifluoromethylphenyldimethylthiocarbamate

If the procedure described in Preparation XI is followed starting from3.95 g (24.3.10⁻³ mol) of 2-trifluoromethylphenol, 1.43 g (25.6.10⁻³mol) of potassium hydroxide and 3.46 g (28.10⁻³ mol) ofdimethylthiocarbamoyl chloride, 5.37 g (yield: 89%) of a yellow oil areobtained.

n_(D) ²⁴.5° C. =1.528

PREPARATION L Preparation of S-2-trifluoromethylphenyldimethylthiocarbamate

If the procedure described in Preparation XII is followed starting from5.37 g (21.5.10⁻³ mol) of O-2-trifluoromethylphenyldimethylthiocarbamate, 3.2 g (yield: 60%) of the expected product areobtained after purification by flash chromatography using atoluene/ethyl acetate mixture (98/2 v/v) as the eluent.

n_(D) ²⁵° C. =1.5182

PREPARATION LI Preparation of 2-trifluoromethylbenzenethiol

If the procedure described in Preparation XIII is followed starting from2.72 g (10.9.10⁻³ mol) of S-2-trifluoromethylphenyldimethylthiocarbamate, 2 g (quantitative yield) of the expected productare obtained.

PREPARATION LII Preparation of 2-trifluoromethylphenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 13a)

If the procedure described in Preparation I is followed starting from1.8 g (10.10⁻³ mol) of 2-trifluoromethylbenzenethiol, 2.55 g (10.10⁻³mol) of mercuric cyanide (Hg(CN)₂) and 3.95 g (11.10⁻³ mol) of2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 1.53 g (yield: 34%)of the expected product are obtained.

M.p.=152° C.

[α]_(D) ²⁰° C. =+64° (c=0.5; CH₃ OH)

PREPARATION LIII Preparation of 2-trifluoromethylphenyl1,5-dithio-β-D-xylopyranoside (Example 13)

If the procedure described in Preparation V is followed starting from1.38 g (3.10⁻³ mol) of 2-trifluoromethylphenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 13a), 0.75 g(yield: 75%) of the expected product is obtained after recrystallizationfrom a methanol/water mixture (1/1 v/v).

M.p.=114°-115° C.

[α]_(D) ²⁰° C. =+34° (c=0.5; CH₃ OH)

PREPARATION LIV Preparation of 4-(4-iodophenyl)benzonitrile

A mixture of 15 g (33.2.10⁻³ mol) of 4,4'-diiodo-1,1'-biphenyl, 3.13 g(34.9.10⁻³ mol) of mercuric cyanide and 2.75 g (34.9.10⁻³ mol) ofpyridine is heated at 200° C. for 15 minutes and 6 ml ofdimethylformamide are then added to the mixture. After cooling, thereaction medium is hydrolyzed with a 1N aqueous solution of hydrochloricacid. The expected product is extracted with ethyl acetate. The organicphase obtained is washed with water until the pH of the washings isneutral, dried over magnesium sulfate and evaporated under vacuum. 3.28g (yield: 33%) of a yellow solid are obtained after purification byflash chromatography using a chloroform/toluene mixture (1/1 v/v) as theeluent.

M.p.=162°-168° C.

PREPARATION LV Preparation of 4-(4-mercaptophenyl)benzonitrile

3.25 g (10.8.10⁻³ mol) of 4-(4-iodophenyl)benzonitrile are dissolved in50 ml of hexamethylphosphoramide, and 3.05 g (43.4.10⁻³ mol) of sodiumthiomethylate are then added to the solution. The reaction mixture isheated at 100° C. for 1.5 hours and then, after cooling, hydrolyzed in a1N hydrochloric acid/ice mixture. The expected product is extracted withethyl acetate. The resulting organic phase is washed with water untilthe pH of the washings is neutral, dried over magnesium sulfate and thenevaporated under reduced pressure to give 2.4 g (quantitative yield) ofa pale yellow solid.

M.p.=105°-115° C.

PREPARATION LVI Preparation of 4-(4-cyanophenyl)phenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 14a)

If the procedure described in Preparation I is followed starting from2.3 g (10.9.10⁻³ mol) of 4-(4-mercaptophenyl)benzonitrile, 4.26 g(11.9.10⁻³ mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromideand 2.75 g (10.9.10⁻³ mol) of mercuric cyanide (Hg(CN)₂), 0.540 g(yield: 10%) of the expected product is obtained after purification byflash chromatography using methylene chloride as the eluent.

M.p.=150° C.

[α]D²⁰° C. =+10.2° (c=0.5; CHCl₃)

PREPARATION LVII Preparation of 4-(4-cyanophenyl)phenyl1,5-dithio-β-D-xylopyranoside (Example 14)

If the procedure described in Preparation V is followed starting from0.340 g (70.1.10⁻³ mol) of 4-(4-cyanophenyl)phenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 14a) and 17 mlof sodium methylate (8% w/v solution of Na in methanol), 0.200 g (yield:80%) of the expected product is obtained after purification byrecrystallization from methanol.

M.p.=168° C.

[α]D²⁰° C.=+5.4° (c=0.5; CH₃ OH/CH₃ Cl (1/1 v/v))

PREPARATION LVIII Preparation of O-3,5-bis(trifluoromethyl)phenyldimethylthiocarbamate

0.975 g (17.4.10⁻³ mol) of potassium hydroxide pellets is dissolved in60 ml of water, 3.81 g (16.5.10⁻³ mol) of3,5-bis(trifluoromethyl)benzenethiol are then added and the mixtureobtained is stirred for 20 minutes at room temperature. A solution of2.35 g (19.10⁻³ mol) of dimethylthiocarbamoyl chloride in 60 ml ofacetone is then added dropwise, after which the resulting solution isstirred for 30 minutes at room temperature. The reaction medium ishydrolyzed in a mixture of ice and 1N hydrochloric acid and thenextracted with ethyl acetate. The organic phase is washed with wateruntil the pH of the washings is neutral, dried over magnesium sulfate,decolorized with animal charcoal and evaporated under reduced pressureto give 4.81 g of the expected product (yield: 92%) in the form of apale yellow solid.

M.p.=71°-80° C.

PREPARATION LIX Preparation of S-3,5-bis(trifluoromethyl)phenyldimethylthiocarbamate

4.81 g (15.10⁻³ mol) of O-3,5-bis(trifluoromethyl)phenyldimethylthiocarbamate are heated at 200°-210° C. for 2 hours to give2.81 g (yield: 58.4%) of the expected product in the form of a yellowoil.

nD²⁵° C.=1.4710

PREPARATION LX Preparation of 3,5-bis(trifluoromethyl)benzenethiol

2.25 g (7.1.10⁻³ mol) of S-3,5-bis(trifluoromethyl)phenyldimethylthiocarbamate are dissolved in 2.2 ml of anhydrousdimethylformamide. The resulting solution is cooled to 0° C. before theaddition of 4 ml (14.10⁻³ mol) of sodium methylate dissolved inmethanol, and is then stirred at 0° C. for 10 minutes. The reactionmedium is subsequently hydrolyzed with an ice/water/1N HCl mixture andthen extracted with methylene chloride. The organic phase obtained iswashed with a saturated solution of sodium chloride, dried overmagnesium sulfate and evaporated under reduced pressure to give 1.74 g(yield: 100%) of the expected product in the form of a yellow oil, whichcrystallizes and dimerizes under the action of heat.

Melting point of the dimer=71° C.

PREPARATION LXI Preparation of 3,5-bis(trifluoromethyl)phenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 15a)

If the procedure described in Preparation I is followed starting from1.6 g (6.5.10⁻³ mol) of 3,5-bis(trifluoromethyl)benzenethiol, 1.64 g(6.5.10⁻³ mol) of mercuric cyanide, Hg(CN)₂, and 2.54 g (7.5.10⁻³ mol)of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 1.2 g (yield:35.7%) of the expected product are obtained.

M.p.=201° C.

[α]D²⁰° C.=+6° (c=0.5; CHCl₃)

PREPARATION LXII Preparation of 3,5-bis(trifluoromethyl)phenyl1,5-dithio-β-D-xylopyranoside (Example 15)

If the procedure described in Preparation V is followed starting from1.1 g (2.1.10⁻³ mol) of 3,5-bis(trifluoromethyl)phenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside, 0.600 g (yield: 72%)of the expected product is obtained after recrystallization from amethanol/water mixture (1/1 v/v).

M.p.=157°-158° C.

[α]D²⁰° C.=+3° (c=0.5; CH₃ OH)

PREPARATION LXIII Preparation of 3-cyano-4-mercaptobenzonitrile

Under argon, 3.03 g (12.10⁻³ mol) of 3-cyano-4-iodobenzonitrile and 3.36g (48.10⁻³ mol) of sodium thiomethylate are dissolved in 80 ml ofanhydrous hexamethylphosphoramide and the solution obtained is thenheated at 80° C. for 45 minutes. The resulting reaction medium ishydrolyzed in an ice/1N HCl mixture and then extracted with methylenechloride. The organic phase is washed with water and then dried overmagnesium sulfate and evaporated under reduced pressure to give 1.55 g(yield: 81%) of the expected product.

M.p.=180° C.

PREPARATION LXIV Preparation of 2,4-dicyanophenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 16a)

If the procedure described in Preparation I is followed starting from1.5 g (9.10⁻³ mol) of 3-cyano-4-mercaptobenzonitrile, 2.78 g (11.10⁻³mol) of mercuric cyanide, Hg(CN)₂, and 3.66 g (11.10⁻³ mol) of2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 1.65 g (yield:40.5%) of the expected product are obtained.

M.p.=228° C.

[α]D²⁰° C.=-14° (c=0.39; CHCl₃)

PREPARATION LXV Preparation of 2,4-dicyanophenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 16a)

If the procedure described in Preparation IV is followed starting from1.6 g (9.73.10⁻³ mol) of 3-cyano-4-mercaptobenzonitrile, 4.07 g(11.45.10⁻³ mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromideand 0.84 g (10.10⁻³ mol) of zinc oxide (ZnO), 2.08 g (yield: 47%) of theexpected product are obtained.

M.p.=228° C.

PREPARATION LXVI Preparation of 2,4-dicyanophenyl1,5-dithio-β-D-xylopyranoside (Example 16)

If the procedure described in Preparation V is followed, except that thereaction is carried out at 0° C., starting from 1.5 g (34.10⁻³ mol) of2,4-dicyanophenyl 2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside(Example 16a), 0.71 g (yield: 67%) of the expected product is obtainedafter chromatography on silica using a CH₂ Cl₂ /CH₃ OH mixture (8/1 v/v)as the eluent.

M.p.=180°-181° C.

[α]D²⁰° C.=+42.7° (c=0.48; CH₃ OH)

PREPARATION LXVII Preparation of 3,5-dicyano-2-mercaptobenzonitrile

If the procedure described in Preparation LV is followed starting from 6g (26.10⁻³ mol) of 2-bromo-3,5-dicyanobenzonitrile and 6 g (86.10⁻³ mol)of sodium thiomethylate, 6 g (quantitative yield) of the expectedproduct are obtained in the form of an oil.

nD²⁹.5° C.=1.5012

PREPARATION LXVIII Preparation of 2,4,6-tricyanophenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 17a)

If the procedure described in Preparation I is followed starting from4.8 g (258.10⁻³ mol) of 3,5-dicyano-2-mercaptobenzonitrile (Example17a), 9.71 g (258.10⁻³ mol) of2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 6.57 g (8.6.10⁻³mol) of mercuric cyanide (Hg(CN)₂), 2 g (yield: 17%) of the expectedproduct are obtained after crystallization from ether.

M.p.=221° C.

[α]D²⁰° C.=+84.6° (c=0.325; CHCl₃)

PREPARATION LXIX Preparation of 2,4,6-tricyanophenyl1,5-dithio-β-D-xylopyranoside (Example 17)

0.600 g (1.30.10⁻³ mol) of 2,4,5-tricyanophenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside is suspended in 120 mlof 0.1M Na₂ HPO₄ /NaH₂ PO₄ buffer (pH: 7.35) and 3 drops of Triton® X100(marketed by SIGMA). 30 drops of pork liver esterase [Sigma type I, 3.2Msuspension in (NH₄)₂ SO₄ ] (marketed by SIGMA) are then added and theresulting mixture is stirred at 30°-35° C. for 12 hours. A further 20drops of pork liver esterase and 10 drops of Triton® X100 are added;finally, after stirring for 24 hours, 30 drops of pork liver esteraseare added. The pH is kept at 7.4 by the addition of 1N sodium hydroxidesolution throughout the experiment. After stirring for 84 hours, thereaction mixture is cooled and the expected product is extracted withethyl acetate. The resulting organic phase is washed with brine and thendried over magnesium sulfate and evaporated under reduced pressure. 100mg (yield: 23%) of the expected product are obtained in the form of afoam after purification by flash chromatography using a CHCl₃ /CH₃ OHmixture (98/2 v/v, then 95/5 v/v) as the eluent. It is a hydratedproduct containing 1.3 H₂ O per molecule.

M.p.=86°-96° C.

[α]D²⁰° C.=0° (c=0.165; CH₃ OH)

PREPARATION LXX Preparation of 4-aminophenyl1,5-dithio-β-D-xylopyranoside (Example 18)

170 mg of 10% palladium-on-charcoal are added to a solution of 1.7 g(5.61.10⁻³ mol) of 4-nitrophenyl 1,5-dithio-β-D-xylopyranoside in 150 mlof methanol. The reaction medium is kept under hydrogen pressure(3.5.10⁵ Pa) at room temperature for 3 days. Repeat amounts of 170 mg of10% palladium-on-charcoal are added after stirring for 3 hours, 4 hours,12 hours and 24 hours. The mixture obtained is filtered, the solvent isevaporated off under reduced pressure and the residue obtained ispurified by flash chromatography using a CHCl₃ /CH₃ OH mixture (9/1 v/v)as the eluent, and is then recrystallized from water to give 0.7 g(yield: 46%) of the expected product.

M.p.=163°-166° C.

[α]D²³° C.=-74° (c=0.102; DMSO)

PREPARATION LXXI Preparation of 4-acetamidophenyl2,3,4-tri-O-acetyl-1,5dithio-β-D-xylopyranoside (Example 19a)

If the procedure described in Preparation IV is followed starting from4.5 g (27.10⁻³ mol) of N-(4-mercaptophenyl)acetamide, 11.43 g (32.10⁻³mol) of 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide and 2.16 g(27.10⁻³ mol) of zinc oxide (ZnO), 3 g (yield: 25%) of the expectedproduct are obtained after recrystallization from a toluene/isopropylether mixture.

M.p.=168°-174° C.

[α]D²³° C.=+8° (c=0.5; CHCl₃)

PREPARATION LXXII Preparation of 4-acetamidophenyl1,5-dithio-β-D-xylopyranoside (Example 19)

If the procedure described in Preparation V is followed starting from1.05 g (2.38.10⁻³ mol) of 4-acetamidophenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 19a), 0.61 g(yield: 81%) of the expected product is obtained after recrystallizationfrom 70 ml of water.

M.p.=226°-233° C.

[α]D²³° C.=-25.25° (c=0.59; DMSO)

PREPARATION LXXIII Preparation of 4-trifluoroacetylphenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 20a)

If the procedure described in Preparation I is followed starting from9.03 g (43.8.10⁻³ mol) of 2,2,2-trifluoro-1-(4-mercaptophenyl)ethanone,11.5 g (45.5.10⁻³ mol) of mercuric cyanide and 17.1 g (48.2.10⁻³ mol) of2,3,4-tri-O-acetyl-1-bromo-5-thio-D-xylopyranoside, 4.79 g (yield: 22%)of the expected product are obtained after purification by flashchromatography using a toluene/ether mixture (8/2 v/v) as the eluent,and recrystallization from ether.

M.p.=143°-148° C.

[α]D²⁴° C.=+59.3° (c=0.28; CHCl₃)

PREPARATION LXXIV Preparation of 4-trifluoroacetylphenyl1,5-dithio-β-D-xylopyranoside (Example 20)

If the procedure described in Preparation V is followed starting from3.65 g (7.6.10⁻³ mol) of 4-trifluoroacetylphenyl2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 20a), 1.4 g(yield: 52%) of the expected product are obtained after purification byrecrystallization from a toluene/n-propyl alcohol/hexane mixture.

M.p.=133°-134° C.

[α]D²²° C.=+15° (c=0.31; CH₃ OH)

PREPARATION LXXV Preparation of 3-aminophenyl1,5-dithio-β-D-xylopyranoside (Example 21)

If the procedure described in Preparation LXX is followed starting from2.9 g (9.6.10⁻³ mol) of 3-nitrophenyl 1,5-dithio-β-D-xylopyranoside, 1.2g (yield: 46%) of the expected product are obtained after purificationby flash chromatography using a CHCl₃ /CH₃ OH mixture as the eluent(solvent proportions from 95/5 to 92/8 v/v), and precipitation in a CH₃OH/ether mixture.

M.p.=128°-132° C.

[α]D²⁵° C.=+3.5° (c=0.31; CH₃ OH)

PREPARATION LXXVI Preparation of 4-cyanophenyl2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside (Example 22a)

A suspension of 6.5 g (12.3.10⁻³ mol) of2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 6 g (50.4.10⁻³ mol)of 4-hydroxybenzonitrile, 6.9 g (50.5.10⁻³ mol) of zinc chloride and 4.4g (25.1.10⁻³ mol) of silver imidazolate in 200 ml of anhydrous methylenechloride is stirred at 40° C., under an inert atmosphere, in the absenceof light and in the presence of a molecular sieve (400 pm). After 7 h atthis temperature, 6.9 g (50.5.10⁻³ mol) of zinc chloride, 4.4 g(25.1.10⁻³ mol) of silver imidazolate and 6.5 g (18.3.10⁻³ mol) of2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide are added. Thereaction medium is left overnight under these conditions and 6.5 g(12.3.10⁻³ mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromideare then added. After 24 h, the reaction mixture is filtered on Celite®, washed with a 1N aqueous solution of hydrochloric acid and then waterand dried over magnesium sulfate. After evaporation under reducedpressure, the residue is purified by chromatography on silica gel usinga hexane/ethyl acetate mixture (3/1 v/v) as the eluent. 8.1 g (yield:41%) of the expected product are obtained by crystallization fromethanol.

M.p.=145°-148° C.

[α]D²¹° C.=-29° (c=0.47; CHCl₃)

PREPARATION LXXVII Preparation of2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranosyl bromide

3.50 ml of a 30% solution of hydrobromic acid in glacial acetic acid areadded at 10° C. to a solution of 2.10 g (6.3.10⁻³ mol) of1,2,3,4-tetra-O-acetyl-5-thio-D-xylopyranose in 10 cm³ ofdichloroethane. After 2 to 3 h, the reaction medium is hydrolyzed,washed with a solution of sodium bicarbonate and dried over sodiumsulfate (Na₂ SO₄) and the solvent is evaporated off to dryness underreduced pressure. 0.87 g (yield: 39%) of the expected product isobtained after precipitation in ether.

M.p.=175° C.

[α]D²¹° C.=-67° (c=0.56; CHCl₃)

PREPARATION LXXVIII Preparation of 4-cyanophenyl2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside (Example 22a)

A suspension of 0.5 g (1.4.10⁻³ mol) of2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide, 0.25 g (2.1.10⁻³ mol)of 4-hydroxybenzonitrile and 170 mg (2.1.10⁻³ mol) of zinc oxide (ZnO)in 4 ml of anhydrous toluene and 4 ml of acetonitrile is stirred at 50°C., under an inert atmosphere, in the presence of a molecular sieve (1nm), for 48 h. The reaction medium is subsequently filtered on Celite®in ethyl acetate and then washed with a 1N aqueous solution ofhydrochloric acid, water, a 1N solution of sodium hydroxide and then asaturated solution of NaCl. The solution obtained is dried over sodiumsulfate and the solvent is evaporated off under reduced pressure. Theresidue obtained is purified by chromatography on silica gel using ahexane/ethyl acetate mixture (2/1 v/v) as the eluent to give 194 mg(yield: 35%) of the expected product.

M.p.=145°-148° C.

PREPARATION LXXIX Preparation of2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranose

22 ml (0.2 mol) of benzylamine are added under an inert atmosphere to asolution of 15 g (44.8.10⁻³ mol) of1,2,3,4-tetra-O-acetyl-5-thio-D-xylopyranose in 450 ml of ether. After 7hours at room temperature (15°-25° C.), the reaction mixture isconcentrated under reduced pressure and the residue is dissolved inmethylene chloride and washed with a 1N solution of hydrochloric acid, asaturated solution of ammonium chloride and then water. The solutionobtained is dried over sodium sulfate and the solvent is evaporated offunder reduced pressure. 6.2 g (yield: 47%) of the expected product areobtained after purification by chromatography on silica gel using ahexane/ethyl acetate mixture (3/2 v/v) as the eluent, andcrystallization from an ethyl acetate/hexane mixture, said producthaving the following physical characteristics:

M.p.=115° C.

[α]D²¹° C. =+131° (c=0.34; CHCl₃)

PREPARATION LXXX Preparation of2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl trichloroacetimidate

1.5 ml (15.10⁻³ mol) of trichloroacetonitrile and 70 mg of NaH (2.3.10⁻³mol of NaH in 80% dispersion) are added to a solution of 1 g (3.42.10⁻³mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranose in 10 ml of methylenechloride. After 4 h at room temperature, the reaction medium is filteredon silica in methylene chloride and then purified by chromatography onsilica gel using a hexane/ethyl acetate mixture (3/1 v/v) as the eluent.790 mg (yield: 53%) of the expected product are obtained aftercrystallization from an ethyl acetate/hexane mixture.

M.p.=110° C.

[α]D²¹° C. =+227° C. (c=0.42; CHCl₃)

PREPARATION LXXXI Preparation of 4-cyanophenyl2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside (Example 22a)

1 ml of a 0.1M solution of boron trifluoride etherate in methylenechloride is added at -15° C., under an inert atmosphere, to a suspensionof 250 mg (0.57.10⁻³ mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyltrichloroacetimidate, 57 mg (0.48.10⁻³ mol) of 4-hydroxybenzonitrile anda molecular sieve (1 nm) in 10 ml of methylene chloride. The reactionmedium is allowed to return gradually to 0° C. and, after a reactiontime of 3 h, is neutralized with sodium bicarbonate. The reactionmixture is then washed with water and dried over magnesium sulfate,MgSO₄, and the solvent is evaporated off under reduced pressure. 150 mg(yield: 80%) of the expected product are obtained after purification bychromatography on silica gel using a hexane/ethyl acetate mixture (2/1v/v) as the eluent.

M.p.=145°-148° C.

PREPARATION LXXXII Preparation of 4-cyanophenyl5-thio-β-D-xylopyranoside (Example 22)

1.5 ml of a solution of sodium methylate in methanol (8% w/v of Na) areadded under an inert atmosphere to a suspension of 10 g (25.4.10⁻³ ) of4-cyanophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside in 200 ml ofmethanol. The reaction mixture is stirred at room temperature for 30min, neutralized by the addition of Amberlite® IR 120 H⁺ resin andfiltered. After evaporation to dryness, the residue is crystallized frommethanol to give 8.8 g (yield: 73%) of the expected product.

M.p.=179°-186° C.

[α]D²¹° C. =-108.6° (c=0.48; CH₃ OH)

PREPARATION LXXXIII Preparation of 4-nitrophenyl2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside (Example 23a)

A suspension of 5.6 g (15.8.10⁻³ mol) of2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 2 g (14.3.10⁻³ mol)of 4-nitrophenol, 4 g (29.3.10⁻³ mol) of zinc chloride and 3.8 g(21.7.10⁻³ mol) of silver imidazolate in 80 ml of anhydrous methylenechloride is stirred at 50° C., under an inert atmosphere, in the absenceof light and in the presence of a molecular sieve (400 pm). After 48 hat this temperature, the reaction mixture is filtered on Celite®, washedwith a 1N aqueous solution of hydrochloric acid, then a 1N solution ofsodium hydroxide and finally water and dried over magnesium sulfate(MgSO₄). After evaporation to dryness, the residue is purified bychromatography on silica gel using a hexane/ethyl acetate mixture (3/1v/v) as the eluent. 1.5 g (yield: 25%) of the expected product areobtained by precipitation in ether.

M.p.=212° C.

[α]D²¹° C. =-78° (c=0.5; CHCl₃)

PREPARATION LXXXIV Preparation of 4-nitrophenyl5-thio-β-D-xylopyranoside (Example 23)

0.2 ml of a solution of sodium methylate in methanol (8% w/v of Na) isadded under an inert atmosphere to a suspension of 1.1 g (2.6.10⁻³ mol)of 4-nitrophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside in 30 mlof methanol. After complete solubilization (2 h), the reaction mixtureis neutralized by the addition of Amberlite® IR 120 H⁺ resin and thenfiltered. 620 mg (yield: 79%) of the expected product are obtained afterevaporation to dryness and lyophilization.

M.p.=130°-132° C.

[α]D²¹° C. =-77.3° (c=0.49; CH₃ OH)

PREPARATION LXXXV Preparation of 4-acetylphenyl2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside (Example 24a)

If the procedure described in Preparation LXXXIII is followed startingfrom 2 g (14.7.10⁻³ mol) of 1-(4-hydroxyphenyl)ethanone, 2.8 g (16.10⁻³mol) of silver imidazolate, 5.74 g (16.1.10⁻³ mol) of2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 4 g (29.3.10⁻³mol) of zinc chloride in 100 ml of methylene chloride, 0.96 g (yield:18%) of the expected product is obtained after purification bychromatography on silica gel using a toluene/ethyl acetate mixture (6/1v/v) as the eluent.

M.p.=156° C.

[α]D²¹° C. =-77° (c=0.5; CHCl₃)

PREPARATION LXXXVI Preparation of 4-acetylphenyl2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside (Example 24a)

If the procedure described in Preparation LXXXI is followed startingfrom 380 mg (0.882.10⁻³ mol) of2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl trichloroacetimidate, 100 mg(73.5.10⁻³ mol) of 1-(4-hydroxyphenyl)ethanone and 1.47 ml of a 0.1Msolution of boron trifluoride etherate in methylene chloride, 140 mg(yield: 47%) of the expected product are obtained after crystallizationfrom ether.

M.p.=156° C.

PREPARATION LXXXVII Preparation of 4-acetylphenyl5-thio-β-D-xylopyranoside (Example 24)

If the procedure described in Preparation LXXXIV is followed startingfrom 0.9 g (2.2.10⁻³ mol) of 4-acetylphenyl2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 0.8 ml of a solution ofsodium methylate in methanol (8% w/v of Na), reacted in 50 ml ofmethanol for 1 h, 0.55 g (yield: 88%) of the expected product isobtained after lyophilization.

M.p.=195°-198° C.

[α]D²¹° C. =-84.5° (c=0.49; CH₃ OH)

PREPARATION LXXXVIII Preparation of 3-acetylphenyl2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside (Example 25a)

If the procedure described in Preparation LXXXIII is followed startingfrom 3.45 g (25.3.10⁻³ mol) of 1-(3-hydroxyphenyl)ethanone, 6 g(16.9.10⁻³ mol) of 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide, 3g (17.10⁻³ mol) of silver imidazolate and 4.6 g (33.7.10⁻³ mol) of zincchloride in 90 ml of methylene chloride and 30 ml of acetonitrile, 0.96g (yield: 14%) of the expected product is obtained after purification bychromatography on silica gel using a toluene/ethyl acetate mixture (6/1v/v) as the eluent, and crystallization from ether.

M.p.=150°-153° C.

[α]D²¹° C. =-81.5° (c=0.5; CHCl₃)

PREPARATION LXXXIX Preparation of 3-acetylphenyl5-thio-β-D-xylopyranoside (Example 25)

If the procedure described in Preparation LXXXIV is followed startingfrom 1.36 g (3.3.10⁻³ mol) of 3-acetylphenyl2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 0.2 ml of a solution ofsodium methylate in methanol (8% w/v of Na), reacted in 50 ml ofmethanol for 30 min, 0.8 g (yield: 85%) of the expected product isobtained after crystallization from an ethanol/ether mixture.

M.p.=166°-174° C.

[α]D²¹° C. =-109° (c=0.42; CH₃ OH)

PREPARATION XC Preparation of 2-cyanophenyl2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside (Example 26a)

If the procedure described in Preparation LXXXIII is followed startingfrom 2 g (16.8.10⁻³ mol) of 2-hydroxybenzonitrile, 4.4 g (25.1.10⁻³ mol)of silver imidazolate, 6.5 g (18.3.10⁻³ mol) of2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 4.6 g (33.6.10⁻³mol) of zinc chloride in 80 ml of methylene chloride, 1.32 g (yield:20%) of the expected product are obtained after purification bychromatography on silica gel using a toluene/ethyl acetate mixture (6/1v/v) as the eluent, and precipitation in ether.

M.p.=176° C.

[α]D²¹° C. =-160° (c=0.45; CHCl₃)

PREPARATION XCI Preparation of 2-cyanophenyl 5-thio-β-D-xylopyranoside(Example 26)

If the procedure described in Preparation LXXXIV is followed startingfrom 1.26 g (3.2.10⁻³ mol) of 2-cyanophenyl2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 0.2 ml of a solution ofsodium methylate in methanol (8% w/v of Na), reacted in 70 ml ofmethanol for 30 min, 0.75 g (yield: 88%) of the expected product isobtained after precipitation in ether and lyophilization.

M.p.=130°-132° C.

[α]D²¹° C. =-68.8° (c=0.485; CH₃ OH)

PREPARATION XCII Preparation of 3-cyanophenyl2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside (Example 27a)

If the procedure described in Preparation LXXXIII is followed startingfrom 2 g (16.8.10⁻³ mol) of 3-hydroxybenzonitrile, 2.9 mg (16.5.10⁻³mol) of silver imidazolate, 6.5 g (18.3.10⁻³ mol) of2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 4.6 g (33.6.10⁻³mol) of zinc chloride in 80 ml of methylene chloride, 2.2 g (yield: 33%)of the expected product are obtained after purification bychromatography on silica gel using a hexane/ethyl acetate mixture (3/1v/v) as the eluent, and precipitation in ether.

M.p.=148°-151° C.

[α]D²¹° C. =-82° (c=0.31; CHCl₃)

PREPARATION XCIII Preparation of 3-cyanophenyl2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside (Example 27a)

If the procedure described in Preparation LXXVIII is followed startingfrom 0.5 g (1.4.10⁻³ mol) of 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosylbromide, 0.25 g (2.1.10⁻³ mol) of 3-hydroxybenzonitrile and 170 mg(2.1.10⁻³ mol) of zinc oxide (ZnO) in 4 ml of anhydrous toluene and 4 mlof acetonitrile, 138 mg (yield: 25%) of the expected product areobtained after purification by chromatography on silica gel using ahexane/ethyl acetate mixture (2/1 v/v) as the eluent, and precipitationin ether.

M.p.=148°-151° C.

PREPARATION XCIV Preparation of 3-cyanophenyl 5-thio-β-D-xylopyranoside(Example 27)

If the procedure described in Preparation LXXXIV is followed startingfrom 2.12 g (5.4.10⁻³ mol) of 3-cyanophenyl2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 0.2 ml of a solution ofsodium methylate in methanol (8% w/v of Na), reacted in 60 ml ofmethanol for 30 min, 1.22 g (yield: 85%) of the expected product areobtained after precipitation in ether and lyophilization.

M.p.=130°-135° C.

[α]D²¹° C. =-107.4° (c=0.47; CH₃ OH)

PREPARATION XCV Preparation of 2-nitrophenyl2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside (Example 28a)

If the procedure described in Preparation LXXXIII is followed startingfrom 2 g (14.4.10⁻³ mol) of 2-nitrophenol, 2.5 g (14.2.10⁻³ mol) ofsilver imidazolate, 6 g (15.7.10⁻³ mol) of2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 4 g (29.3.10⁻³mol) of zinc chloride in 80 ml of methylene chloride, 0.91 g (yield:15%) of the expected product is obtained after purification bychromatography on silica gel using a hexane/ethyl acetate mixture (2/1v/v) as the eluent, and precipitation in ether.

M.p.=148° C.

[α]D²¹° C. =-102.8° (c=0.40; CHCl₃)

PREPARATION XCVI Preparation of 2-nitrophenyl 5-thio-β-D-xylopyranoside(Example 28)

If the procedure described in Preparation LXXXIV is followed startingfrom 0.85 g (2.05.10⁻³ mol) of 2-nitrophenyl2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 0.1 ml of a solution ofsodium methylate in methanol (8% w/v of Na), reacted in 50 ml ofmethanol for 30 min, 0.4 g (yield: 68%) of the expected product isobtained after precipitation in ether and lyophilization.

M.p.=137°-140° C.

[α]D²¹° C. =-117° (c=0.35; CH₃ OH)

PREPARATION XCVII Preparation of 2-acetylphenyl2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside (Example 29a)

If the procedure described in Preparation LXXXIII is followed startingfrom 3.45 g (25.3.10⁻³ mol) of 1-(2-hydroxyphenyl)ethanone, 6 g(16.9.10⁻³ mol) of 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide, 3g (17.10⁻³ mol) of silver imidazolate and 4.6 g (33.7.10⁻³ mol) of zincchloride in 90 ml of methylene chloride and 30 ml of acetonitrile, 0.92g (yield: 13.5%) of the expected product is obtained after purificationby chromatography on silica gel using a toluene/ethyl acetate mixture(6/1 v/v) as the eluent, and crystallization from ether.

M.p.=112° C.

[α]D²¹° C. =-100° (c=0.42; CHCl₃)

PREPARATION XCVIII Preparation of 2-acetylphenyl5-thio-β-D-xylopyranoside (Example 29)

If the procedure described in Preparation LXXXIV is followed startingfrom 0.88 g (2.1.10⁻³ mol) of 2-acetylphenyl2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 0.1 ml of a solution ofsodium methylate in methanol (8% w/v of Na), reacted in 50 ml ofmethanol for 30 min, 0.51 g (yield: 84%) of the expected product isobtained after purification by chromatography on silica gel using achloroform/methanol mixture (12/1 v/v) as the eluent, andlyophilization.

M.p.=102°-105° C.

[α]D²¹° C. =-90° (c=0.44; CH₃ OH)

PREPARATION IC Preparation of 2-(6-cyanonaphthalenyl)2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside (Example 30a)

If the procedure described in Preparation LXXXIII is followed startingfrom 1.69 g (10.10⁻³ mol) of 6-hydroxynaphthalene-2-carbonitrile, 1.75 g(10.10⁻³ mol) of silver imidazolate, 3.87 g (11.1.10⁻³ mol) of2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 2.7 g (19.7.10⁻³mol) of zinc chloride in 80 ml of methylene chloride, 0.72 g (yield:16%) of the expected product is obtained after purification bychromatography on silica gel using a hexane/ethyl acetate mixture (3/1v/v) as the eluent, and precipitation in ether.

M.p.=194° C.

[α]D²¹° C. =-57.4° (c=0.5; CHCl₃)

PREPARATION C Preparation of 2-(6-cyanonaphthalenyl)5-thio-β-D-xylopyranoside (Example 30)

If the procedure described in Preparation LXXXIV is followed startingfrom 0.92 g (2.1.10⁻³ mol) of 2-(6-cyanonaphthalenyl)2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 0.2 ml of a solution ofsodium methylate in methanol (8% w/v of Na), reacted in 40 ml ofmethanol with the addition of tetrahydrofuran until solubilization iscomplete, 0.59 g (yield: 90%) of the expected product is obtained afterprecipitation in ether and crystallization from methanol.

M.p.=209°-214° C.

[α]D²¹° C. =-83° (c=0.2; CH₃ OH)

PREPARATION CI Preparation of 2-(1-cyanonaphthalenyl)2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside (Example 31a)

If the procedure described in Preparation LXXXIII is followed startingfrom 5 g (29.5.10⁻³ mol) of 2-hydroxynaphthalene-1-carbonitrile, 4.8 g(32.7.10⁻³ mol) of silver imidazolate, 10.5 g (29.5.10⁻³ mol) of2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 12 g (88.10⁻³mol) of zinc chloride in 200 ml of methylene chloride, 3.85 g (yield:29.4%) of the expected product are obtained after purification bychromatography on a silica column using a hexane/ethyl acetate mixture(7/3 v/v) as the eluent, followed by washing with ether.

M.p.=192° C. (decomposition)

[α]D²⁴° C.=-141.6° (c=0.3; CHCl₃)

PREPARATION CII Preparation of 2-(1-cyanonaphthalenyl)5-thio-β-D-xylopyranoside (Example 31)

If the procedure described in Preparation LXXXIV is followed startingfrom 3 g (6.76.10⁻³ mol) of 2-(1-cyanonaphthalenyl)2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 1.2 ml of a solution ofsodium methylate in methanol (8% w/v of Na), reacted in 70 ml ofmethanol for 3.5 h, 1.30 g (yield: 59%) of the expected product areobtained after recrystallization from a methanol/water mixture (5/1v/v).

M.p.=163°-164° C.

[α]D²⁴° C. =+13° (c=0.29; CH₃ OH)

PREPARATION CIII Preparation of 4-acetamidophenyl2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside (Example 32a)

30 mg of 10% palladium-on-charcoal are added to a solution of 150 mg(0.36.10⁻³ mol) of 4-nitrophenyl2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside in acetic anhydride, undera nitrogen atmosphere, and the reaction mixture obtained is then keptunder hydrogen pressure (3.5.10⁵ Pa) at 50° C. for 15 hours. Afterfiltration, the mixture is evaporated to dryness under reduced pressureand the residue obtained is purified by chromatography using a methylenechloride/methanol mixture (98/2 v/v) as the eluent to give 80 mg (yield:51%) of the expected product.

M.p.=166° C.

[α]D²⁵° C. =-34° (c=0.25; CHCl₃)

PREPARATION CIV Preparation of 4-acetamidophenyl5-thio-β-D-xylopyranoside (Example 32)

If the procedure described in Preparation LXXXIV is followed startingfrom 1.2 g (2.8.10⁻³ mol) of 4-acetamidophenyl2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 70 μl of a solution ofsodium methylate in methanol (8% w/v of Na), reacted in 100 cm³ ofmethanol, 0.7 g (yield: 83%) of the expected product is obtained afterpurification by flash chromatography using a methylene chloride/methanolmixture (93/7 v/v) as the eluent.

M.p.=238° C.

[α]D²⁵° C. =-48.3° (c=0.145; DMSO)

Without implying a limitation, the compounds according to the inventionhave been collated in Tables I and I bis given below, Table I relatingto the compounds of formula I having a phenylthioxyloside structure andTable I bis relating to the compounds of formula I having anaphthalenylthioxyloside structure.

The antithrombotic activity of the products according to the inventionwas demonstrated by means of the following operating protocol for venousthrombosis:

A venous stasis under hypercoagulation is produced according to thetechnique described by WESSLER et al. (J. Applied Physiol. 1959, p.943-946). As in the technique described by J. HAUPMAN et al. (Thrombosisand Haemostasis 43(2), 1980, p. 118), the hypercoagulant used is asolution of activated factor X (Xa) supplied by Flow Laboratories (71Knat per 12.5 ml of physiological serum).

The study is performed on unfasted male Wistar rats weighing 250 to 280g, divided into groups of 10 animals each. The products to be tested areadministered orally as a suspension in PEG 400. A thrombosis is induced4 hours after this treatment and the thrombus formed is removed andweighed.

The results obtained at doses of 3 mg/kg or 12.5 mg/kg, administeredorally, have been collated in Table II. The results obtained with theknown products of the above-mentioned prior art have also been collatedin this Table.

The venous antithrombotic activity of the products according to theinvention is distinctly superior to that of the known products of theprior art.

                  TABLE I                                                         ______________________________________                                         ##STR11##                     (I)                                            Ex.  X     Y         R.sub.1     R.sub.2                                                                              R.sub.3                               ______________________________________                                         1a  S     COCH.sub.3                                                                              4-CN        H      H                                      1   S     H         4-CN        H      H                                      2a  S     COCH.sub.3                                                                              4-NO.sub.2  H      H                                      2   S     H         4-NO.sub.2  H      H                                      4a  S     COCH.sub.3                                                                              4-CF.sub.3  H      H                                      4   S     H         4-CF.sub.3  H      H                                      5a  S     COCH.sub.3                                                                              3-CN        H      H                                      5   S     COCH.sub.3                                                                              3-CN        H      H                                      6a  S     COCH.sub.3                                                                              2-CN        H      H                                      6   S     H         2-CN        H      H                                      7a  S     COCH.sub.3                                                                              2-NO.sub.2  H      H                                       7  S     H         2-NO.sub.2  H      H                                      9a  S     COCH.sub.3                                                                              H           H      H                                      9   S     H         H           H      H                                     10a  S     COCH.sub.3                                                                              3-OCH.sub.3 4-OCH.sub.3                                                                          5-OCH.sub.3                           10   S     H         3-OCH.sub.3 4-OCH.sub.3                                                                          5-OCH.sub.3                           11a  S     COCH.sub.3                                                                              4-COCH.sub.3                                                                              H      H                                     11   S     H         4-COCH.sub.3                                                                              H      H                                     12a  S     COCH.sub.3                                                                              3-NO.sub.2  H      H                                     12   S     H         3-NO.sub.2  H      H                                     13a  S     COCH.sub.3                                                                              2-CF.sub.3  H      H                                     13   S     H         2-CF.sub.3  H      H                                     14a  S     COCH.sub.3                                                                               ##STR12##  H      H                                     14   S     H                                                                                        ##STR13##  H      H                                     15a  S     COCH.sub.3                                                                              3-CF.sub.3  5-CF.sub.3                                                                           H                                     15   S     H         3-CF.sub.3  5-CF.sub.3                                                                           H                                     16a  S     COCH.sub.3                                                                              2-CN        4-CN   H                                     16   S     H         2-CN        4-CN   H                                     17a  S     COCH.sub.3                                                                              2-CN        4-CN   6-CN                                  17   S     H         2-CN        4-CN   6-CN                                  18   S     H         4-NH.sub.2  H      H                                     19a  S     COCH.sub.3                                                                              4-NHCOCH.sub.3                                                                            H      H                                     19   S     H         4-NHCOCH.sub.3                                                                            H      H                                     20a  S     COCH.sub.3                                                                              4-COCF.sub.3                                                                              H      H                                     20   S     H         4-COCF.sub.3                                                                              H      H                                     21   S     H         3-NH.sub.2  H      H                                     22a  O     COCH.sub.3                                                                              4-CN        H      H                                     22   O     H         4-CN        H      H                                     23a  O     COCH.sub.3                                                                              4-NO.sub.2  H      H                                     23   O     H         4-NO.sub.2  H      H                                     24a  O     COCH.sub.3                                                                              4-COCH.sub.3                                                                              H      H                                     24   O     H         4-COCH.sub.3                                                                              H      H                                     25a  O     COCH.sub.3                                                                              3-COCH.sub.3                                                                              H      H                                     25   O     H         3-COCH.sub.3                                                                              H      H                                     26a  O     COCH.sub.3                                                                              2-CN        H      H                                     26   O     H         2-CN        H      H                                     27a  O     COCH.sub.3                                                                              3-CN        H      H                                     27   O     H         3-CN        H      H                                     28a  O     COCH.sub.3                                                                              2-NO.sub.2  H       H                                    28   O     H         2-NO.sub.2  H      H                                     29a  O     COCH.sub.3                                                                              2-COCH.sub.3                                                                              H      H                                     29   O     H         2-COCH.sub.3                                                                              H      H                                     32a  O     COCH.sub.3                                                                              4-NHCOCH.sub.3                                                                            H      H                                     32   O     H         4-NHCOCH.sub.3                                                                            H      H                                     ______________________________________                                        bis                                                                            ##STR14##                                                                    Ex.    X         Y           R.sub.4 R.sub.5                                  ______________________________________                                         8     S         H           H       CN                                        8a    S         COCH.sub.3  H       CN                                       30     O         H           H       CN                                       30a    O         COCH.sub.3  H       CN                                       31     O         H           CN      H                                        31a    O         COCH.sub.3  CN      H                                        ______________________________________                                    

                  TABLE II                                                        ______________________________________                                                    % inhibition at                                                                           % inhibition at                                       Example     12.5 mg/kg  3 mg/kg                                               ______________________________________                                         1a         90          30                                                     1          90          53                                                     2          78          35                                                     3          38          --                                                     4          66          --                                                     5            79.5      28                                                     6            88.6      35                                                     7            96.7      33                                                     8            94.7      31                                                     9           .sup.  11 (1)                                                                            --                                                     10a        62          --                                                    10            36.5      --                                                    11            98.3      47                                                    12          69          --                                                    13          23          --                                                    14          86          27                                                     16a          72.8      --                                                    16            99.5        42.5                                                17          40           8                                                    18          93          30                                                     19a        --          66                                                    19          93          61                                                    20          --          49                                                    21          --          31                                                     22a        --          66                                                    22          --          57                                                     23a        --          44                                                    23          94            37.5                                                24          100         55                                                     25a        --          52                                                    25          --            44.5                                                26          96            63.5                                                 27a        --          57                                                    27          98          66                                                    28          94          51                                                    29          --          26                                                    30          --          51                                                     31a        --            44.5                                                31          --          28                                                    A            .sup.  14 (2)                                                    B             5.5                                                             ______________________________________                                         A: comparative product described in Example 1 of European patent document     A0133103                                                                      B: comparative product described in Example 97 of European patent documen     B0051023                                                                      (1) 82 to 50 mg/kg administered orally                                        (1) 77 to 50 mg/kg administered orally                                   

What is claimed is:
 1. 4-Acetylphenyl 5-thio-β-D-xylopyranoside. 2.3-Cyanophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside. 3.3-Cyanophenyl 2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside. 4.4-Acetamidophenyl 1,5-dithio-β-D-xylopyranoside.
 5. An acylthioxylosyltrichloroacetimidate of the formula ##STR15## wherein Y is an acetylgroup.
 6. 4-acetylphenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside.